Interferon-gamma-dependent Immunity in Bacillus Calmette-Guérin Vaccine Osteitis Survivors

Abstract

Background Inborn errors of interferon-gamma (IFN-γ) –mediated immunity underlie disseminated disease caused by Mycobacterium bovis Bacillus Calmette-Guérin (BCG) live vaccines. We hypothesized that some patients with osteitis after BCG vaccination may have an impaired IFN-γ immunity. Our aim was to investigate IL-12 and IFN-γ ex-vivo production stimulated with BCG and BCG+IFN-γ or BCG+IL-12, respectively, in BCG osteitis survivors. Methods Fresh blood samples were collected from 132 former BCG osteitis Finnish patients now aged 21-49 years, and IL-12 and IFN-γ were measured in cell cultures with and without stimulation with BCG and with BCG+IFN-γ or BCG+IL-12, respectively. As a pilot study, known disease-causing genes controlling IFN-γ immunity (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, ISG15, IRF8, NEMO and CYBB) were investigated in 20 selected patients by whole-exome -sequencing. Results By the limit of <5th percentile, ex-vivo IL-12 concentration and increase in concentration was low in five, and ex-vivo IFN-γ concentration and increase in concentration was low in six patients (including two samples with both IL-12 and IFN-γ findings). By the limit of <10th percentile, an additional six and four patients were respectively detected (including two samples with both findings). With two exceptions, low concentrations and low increases in concentrations picked-up the same cases. Mutations in known disease-causing IFN-γ-related genes were not found in any of these patients. Conclusion These findings call for searching of mutations in new genes governing IFN-γ-dependent immunity to live BCG vaccine.

Orthopedic Complications in Former Bacillus Calmette-GuÉrin Osteitis Patients

“…Recently, we reported that there was no increased morbidity in chronic infections like tuberculosis or other chronic diseases in this cohort of former BCG osteitis patients. 7 Most previous studies of BCG osteitis patients from other countries have focused only on few patients, and the whole picture of BCG osteitis and its complications has remained unclear. Because of the rarity of the infection, no randomized controlled trials have been conducted to evaluate methods of intervention.…”

Haplotype of the Interleukin 17A gene is associated with osteitis after Bacillus Calmette-Guerin vaccination

“…All BCG osteitis cases were ethnic Finns, and this homogeneity is a benefit in genetic studies. Originally, the total number of BCG osteitis patients was 222, and as published recently, none of them had died of tuberculosis, BCG infection or other severe infection 10 . Thus, the present sample of 130 former BCG patients probably represents well the original BCG osteitis patients at the time when BCG vaccination was offered to all Finnish newborns.…”

“…BCG osteitis was more common in Finland than elsewhere at the time when BCG vaccinations were given to all Finnish newborns. During the years 1960–1988, altogether 222 children suffered from BCG osteitis in infancy 7 , 8 , and in 2008–2009, we collected questionnaire data from 160 of them and blood samples from 132 of them for immunological and genetic studies 9 , 10 .…”

Interleukin 17A gene polymorphism rs2275913 is associated with osteitis after the Bacillus Calmette‐Guérin vaccination

“…They answered a questionnaire that comprised questions on chronic illnesses, long‐term medication, repeated or chronic infections and mycobacterial infections. Whole‐blood samples from 132 of the patients, who lived all over Finland, were sent to the laboratory of the National Institute for Health and Welfare, Turku, Finland . Deoxyribonucleic acid (DNA) was isolated from 200 μ L of whole blood and both DNA and serum samples were frozen at −70°C for further analyses.…”